Molecular studies of the ob and Ay
mutations have provided remarkable insight over the last decade into mechanisms
that balance energy intake with energy expenditure. Leptin is the afferent arm
of a homeostatic circuit in which neuropeptides produced in the hypothalamus
act via the Melanocortin 4 receptor (Mc4r) to initiate compensatory responses
to energy deprivation (leptin and/or caloric deficiency) or energy excess. Leptin-deficiency
(in ob/ob mice) and Mc4r blockade (in Ay
mice) both cause obesity but in very different patterns: Ay
mice develop overgrowth and have a relatively mild hypercortisolism whereas
ob/ob mice develop a reduction in lean body mass and exhibit
profound disturbances of the thyroid, reproductive, and HPA axes.

To better understand the difference between these
phenotypes and the relationships between the leptin and central melanocortinergic
pathways we have measured patterns of gene expression in non-mutant, ob/ob,
and Ay mutant mice, either free-fed or fasted for 48 hours.
Gene expression profiles were determined using spotted arrays of mouse cDNAs
from Phase I of the Mouse Encyclopedia, and analyzed with hierarchical clustering.
Of approximately 16,000 genes queried, 900 exhibited changes greater than 2-fold
across the entire data set. In peripheral tissues of normal mice, fasting induces
profound changes in gene expression in which distinct metabolic pathways can
be identified including fatty acid biosynthesis, oxidative phosphorylation,
and protein catabolism.

Gene expression patterns in ob/ob
mice are nearly identical to fasted non-mutant mice, whereas gene expression
patterns in Aymice are nearly identical to free-fed non-mutant
mice. Thus, the difference between the mutant phenotypes is most easily explained
by changes in energy balance perception: Ay animals fail
to respond to starvation whereas ob/ob behave as though they
are starving even when they are not. Because the patterns of gene expression
are not affected by fasting in either mutant, signals emanating from the leptin
or the melanocortinergic systems can override the actual state of energy balance.